Multiple mechanisms of NADPH oxidase inhibition by type A and type B Francisella tularensis

Ramona L. McCaffrey, Justin T. Schwartz, Stephen R. Lindemann, Jessica G. Moreland, Blake W. Buchan, Bradley D. Jones, Lee Ann H Allen

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Ft is a facultative intracellular pathogen that infects many cell types, including neutrophils. In previous work, we demonstrated that the type B Ft strain LVS disrupts NADPH oxidase activity throughout human neutrophils, but how this is achieved is incompletely defined. Here, we used several type A and type B strains to demonstrate that Ft-mediated NADPH oxidase inhibition is more complex than appreciated previously. We confirm that phagosomes containing Ft opsonized with AS exclude flavocytochrome b558 and extend previous results to show that soluble phox proteins were also affected, as indicated by diminished phosphorylation of p47phox and other PKC substrates. However, a different mechanism accounts for the ability of Ft to inhibit neutrophil activation by formyl peptides, Staphylococcus aureus, OpZ, and phorbol esters. In this case, enzyme targeting and assembly were normal, and impaired superoxide production was characterized by sustained membrane accumulation of dysfunctional NADPH oxidase complexes. A similar post-assembly inhibition mechanism also diminished the ability of anti-Ft IS to confer neutrophil activation and bacterial killing, consistent with the limited role for antibodies in host defense during tularemia. Studies of mutants that we generated in the type A Ft strain Schu S4 demonstrate that the regulatory factor fevR is essential for NADPH oxidase inhibition, whereas iglI and iglJ, candidate secretion system effectors, and the acid phosphatase acpA are not. As Ft uses multiple mechanisms to block neutrophil NADPH oxidase activity, our data strongly suggest that this is a central aspect of virulence.

Original languageEnglish (US)
Pages (from-to)791-805
Number of pages15
JournalJournal of Leukocyte Biology
Volume88
Issue number4
DOIs
StatePublished - Oct 2010

Keywords

  • Immune serum
  • Neutrophil
  • Pathogenesis
  • Phosphorylation
  • Respiratory burst
  • Tularemia

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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    McCaffrey, R. L., Schwartz, J. T., Lindemann, S. R., Moreland, J. G., Buchan, B. W., Jones, B. D., & Allen, L. A. H. (2010). Multiple mechanisms of NADPH oxidase inhibition by type A and type B Francisella tularensis. Journal of Leukocyte Biology, 88(4), 791-805. https://doi.org/10.1189/jlb.1209811